In recent years, calcineurin inhibitors such as cyclosporine and FK506 are used to suppress rejection of patients who underwent organ transplantation. However, a certain kind of calcineurin inhibitor such as cyclosporine sometimes causes adverse side effects such as renal toxicity, liver toxicity, neurotoxicity and the like. Therefore, the development of a safer and highly effective medicament is ongoing to suppress rejection of transplant patients.
Patent references 1-4 disclose that amino alcohol compounds are useful as suppressants of (acute or chronic) rejection in organ or bone marrow transplantation, as well as therapeutic drugs for various autoimmune diseases such as psoriasis, Behcet's disease and the like and rheumatism diseases.
Among them, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (hereinafter sometimes to be also referred to as FTY720) is a compound commercially available as a therapeutic drug for multiple sclerosis. FTY720 is rapidly converted to phosphorylated FTY720 [hereinafter sometimes to be also referred to as FTY720-P, for example, 2-amino-2-phosphonooxymethyl-4-(4-octylphenyl)butanol] in vivo by sphingosine kinase. FTY720-P acts as an agonist of 4 kinds of S1P receptors (other than S1P2) out of 5 kinds of sphingosine-1-phosphate (hereinafter to be sometimes referred to as S1P) receptors (hereinafter to be sometimes referred to as S1P1-5, respectively) (non-patent document 1).
Recently, it has been suggested that S1P1 in S1P receptors is essential for the emigration of mature lymphocytes from thymus and secondary lymphoid tissues. FTY720-P acts as an S1P1 agonist to down-regulate S1P1 on lymphocytes. As a result, the emigration of mature lymphocytes from thymus and secondary lymphoid tissues is inhibited and circulating mature lymphocytes in blood are sequestered in the secondary lymphoid tissues, whereby the immunosuppressive action is exhibited (non-patent document 2).
On the other hand, conventional amino alcohol compounds are feared to show expression of a transient decrease in the heart rate as side effects, and to solve this problem, a number of novel compounds obtained by modifying the chemical structures of amino alcohol compounds have been reported. Among them, patent document 4 discloses an aminopropanol compound wherein the benzene ring contained in FTY720 is a bicyclic structure. In addition, patent document 5 discloses a biphenylether compound, and patent document 6 discloses a biphenylsulfide compound. However, none of the patent documents 4-6 disclose a derivative having a tricyclic structure, nor do they describe that the decrease in the heart rate was alleviated. While patent document 7 discloses that a compound wherein the substituent on the benzene ring contained in FTY720 is a trihaloalkyl group or a cyano group shows a weak heart rate-decreasing action, it does not disclose a derivative having a tricyclic structure.